PROJECT SUMMARY Therapies that redirect T cell specificity to tumors using chimeric antigen receptors or engineered T cell receptors are transforming how we treat cancer. However, most T cell responses are broad programs that encompass elements that are both therapeutic and toxic. The ability to customize and shape immune cell responses could dramatically improve the safety and efficacy of T cell immunotherapy. We have recently developed a novel class of synthetic receptors called synthetic Notch (synNotch) receptors that directly induce a transcriptional response when they recognize a user-specified antigen. SynNotch receptors can control custom transcriptional programs in T cells: they can drive specific T cell gene expression, cytokine secretion profiles, T cell differentiation, and the local delivery of therapeutic payloads in response to recognition of tumor or other disease related antigens. Synthetic Notch T cells are thus a highly versatile platform to more precisely recognize tumors and remodel local tumor microenvironments in a programmable way. Here we will engineer novel therapeutic SynNotch circuits in T cells and other immune cell types (e.g. macrophages) to locally produce cancer therapeutics or immunomodulatory agents in solid tumors. This work will lay the foundation for the use of these cells for customized antigen controlled therapeutic delivery and will be critical to understand the extent that we can utilize therapeutic cells to modulate various features of tumor environments to help elicit a curative immune response. This strategy also has far-reaching implications for the treatment of autoinflammatory diseases, chronic infection, and tissue damage.